One of the primary functions of the brain is to integrate and process sensory input into a form that can guide the behavior of an animal within its environment. Combining sensory information in such a way that the source of a given stimulus can be located is a key aspect of this function. I propose to study the integration and processing of bilateral sensory information as it applies to odor localization in mice. Mice are macrosmotic creatures, and employ their sense of smell to detect conspecifics, food, and predators at a distance. Odor source localization is thus a vital ability for mice. Despite its ethological importance, the neural mechanisms that support odor localization are largely unknown. Research in this proposal will focus upon a cortical structure, the anterior olfactory nucleus (AON), which has been hypothesized to play a central role in odor localization by processing bilateral olfactory information and transmitting this information across the two hemispheres of the brain. First, work performed during the mentored phase will define a functional role for inter-hemispheric feedback projections from the AON to earlier olfactory structures. This will be accomplished by both monitoring the odor responses of these neurons and controlling their activity during odor localization tasks. Selective monitoring of AON feedback projections will be accomplished through cutting edge multiphoton imaging techniques, and the role of these neurons in odor localization will be directly tested using optogenetic strategies. Training in these two techniques will greatly contribute to the experimental repertoire of the candidate. After obtaining this information, work during the independent phase will employ these techniques to elucidate the mechanisms through which bilateral input is processed in the AON, focusing upon the role of inhibitory neurons. Taken together, the results of these studies will define how feedback from the cortex and local cortical inhibitory processing work together to combine bilateral sensory information in such a way that the source of an odor can be identified. By defining the mechanisms used to integrate sensory information in support of an ethologically relevant function, this work will provide a firm basis fr the general understanding of information processing within neural circuits as it occurs during natural sensory-driven behavior. Defining such fundamental mechanisms of neural circuit processing will be instrumental for the understanding and treatment of disorders that alter sensory integration, such as schizophrenia and autism spectrum disorders. Candidate's immediate and long-term career goals The candidate, Dr. David Gire, has experience with research in the olfactory system at both the circuit and systems level, providing a solid background in the methods and concepts related to this proposal. The long term goal of Dr. Gire's career is to define the neural circuit mechanisms used by animals as they process odor cues to obtain information about their environment. To conduct this work, in addition to his current experience, Dr.Gire will need to obtain training in techniques that will allow him to study neural circuit dynamics with high specificity and resolution while these circuits are used to process sensory information in awake, behaving animals. The research training provided in this proposal will involve methods designed to monitor and control specific neural circuit elements in behaving animals. These techniques include multi-photon imaging, head-restrained behavior, precise odor stimulation, and optogenetics. Combined training in these techniques will provide the final set of tools necessary for Dr. Gire to begin an independent research career with a focus upon neural circuit operation in awake, behaving animals. Key elements of the research career development plan The research described in the mentored phase of this proposal will be carried out in the laboratory of Dr. Venkatesh Murthy at Harvard University. The Murthy lab has demonstrated excellence in key areas of the proposal, including multiphoton imaging and optogenetic investigation of the olfactory system. The candidate has also assembled an Advisory Committee to support the successful completion of the training and research in this proposal. This committee includes Drs. Ed Boyden (MIT), Naoshige Uchida (Harvard), and Rachel Wilson (Harvard Medical School). Each committee member will provide specific research expertise and training to the candidate, including direct training in each of the committee members' laboratories. While in the mentored phase, the candidate will meet frequently with his mentor and committee in order to ensure progress with regard to both the research goals of the proposal as well as the candidate's advancement towards becoming an independent investigator. As the candidate begins his independent career, his Advisory Committee will continue to offer support and advice regarding early career issues, which will further support the transition of the candidate to independence.